HIV–TB coinfection impairs CD8+ T‐cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses

Tuberculosis (TB) is the leading cause of death among HIV-positive patients. The decreasing frequencies of terminal effector (T-TE) CD8(+)T cells may increase reactivation risk in persons latently infected with Mycobacterium tuberculosis (Mtb). We have previously shown that dehydroepiandrosterone (DHEA) increases the protective antitubercular immune responses in HIV-TB patients. Here, we aimed to study Mtb-specific cytotoxicity, IFN-gamma secretion, memory status of CD8(+)T cells, and their modulation by DHEA during HIV-TB coinfection. CD8(+)T cells from HIV-TB patients showed a more differentiated phenotype with diminished naive and higher effector memory and T-TE T-cell frequencies compared to healthy donors both in total and Mtb-specific CD8(+)T cells. Notably, CD8(+)T cells from HIV-TB patients displayed higher Terminal Effector (T-TE) CD45RA(dim) proportions with lower CD45RA expression levels, suggesting a not fully differentiated phenotype. Also, PD-1 expression levels on CD8(+)T cells from HIV-TB patients increased although restricted to the CD27(+) population. Interestingly, DHEA plasma levels positively correlated with T-TE in CD8(+)T cells and in vitro DHEA treatment enhanced Mtb-specific cytotoxic responses and terminal differentiation in CD8(+)T cells from HIV-TB patients. Our data suggest that HIV-TB coinfection promotes a deficient CD8(+)T-cell differentiation, whereas DHEA may contribute to improving antitubercular immunity by enhancing CD8(+)T-cell functions during HIV-TB coinfection.